Zheng Haifeng, Nguyen Ha, Nguyen Khoi, Pan Shiyue, Zhou Tong, Nguyen Tin, Earley Yumei Feng
Department of Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Department of Pharmacology & Physiology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
bioRxiv. 2025 Aug 19:2025.08.14.669892. doi: 10.1101/2025.08.14.669892.
The hypothalamic paraventricular nucleus (PVN) integrates neuroendocrine and autonomic signals that regulate blood pressure and metabolism. Although the renin-angiotensin system (RAS) is implicated in neurogenic hypertension and obesity, cell-type-specific expression and regulation of its components within the PVN remain poorly understood. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to profile the transcriptomic landscape of the PVN in male mice under baseline conditions and in models of DOCA-salt-induced hypertension and high-fat diet (HFD)-induced obesity. We identified major PVN cell types, including neurons, astrocytes, precursor oligodendrocytes, oligodendrocytes, microglia and endothelial cells, and further resolved eight transcriptionally distinct neuronal subtypes. Expression of RAS-related genes was highly cell-type specific: (angiotensinogen) was enriched in astrocytes, whereas (angiotensin-converting enzyme), (also known as the (pro)renin receptor [PRR]), (angiotensin II type 1a receptor, aka ATR), (leucyl/cystinyl aminopeptidase, aka angiotensin 4 receptor [ATR]), and the proto-oncogene were predominantly expressed in neurons. DOCA-salt treatment increased the proportion of GABAergic and vasopressin neurons and enhanced neuronal and expression, while reducing astrocytic , suggesting activation of a vasoconstrictive RAS axis. HFD exposure increased excitatory and stress-responsive neuronal subtypes (glutamatergic, vasopressin, corticotropin-releasing hormone) and upregulated , , , and in vasopressin neurons, while downregulating multiple RAS genes in GABAergic neurons. These findings reveal dynamic, cell-type-specific remodeling of RAS signaling in the PVN in response to hypertensive and metabolic stress, providing a transcriptomic atlas of RAS expression in the PVN and identifying potential cellular targets for therapeutic strategies addressing cardiometabolic disorders.
下丘脑室旁核（PVN）整合调节血压和新陈代谢的神经内分泌和自主信号。尽管肾素-血管紧张素系统（RAS）与神经源性高血压和肥胖有关，但其在PVN内细胞类型特异性的表达和调控仍知之甚少。在此，我们采用单核RNA测序（snRNA-seq）来描绘雄性小鼠在基线条件下以及在去氧皮质酮-盐诱导的高血压和高脂饮食（HFD）诱导的肥胖模型中PVN的转录组图谱。我们鉴定出了主要的PVN细胞类型，包括神经元、星形胶质细胞、少突胶质前体细胞、少突胶质细胞、小胶质细胞和内皮细胞，并进一步解析出了8种转录上不同的神经元亚型。RAS相关基因的表达具有高度的细胞类型特异性：血管紧张素原在星形胶质细胞中富集，而血管紧张素转换酶、（也称为（前）肾素受体[PRR]）、血管紧张素II 1a型受体（又名ATR）、亮氨酰/胱氨酰氨肽酶（又名血管紧张素4受体[ATR]）和原癌基因主要在神经元中表达。去氧皮质酮-盐处理增加了GABA能和加压素神经元的比例，并增强了神经元和的表达，同时降低了星形胶质细胞的，表明激活了血管收缩性RAS轴。HFD暴露增加了兴奋性和应激反应性神经元亚型（谷氨酸能、加压素、促肾上腺皮质激素释放激素），并上调了加压素神经元中的、、和，同时下调了GABA能神经元中的多个RAS基因。这些发现揭示了PVN中RAS信号在高血压和代谢应激反应中的动态、细胞类型特异性重塑，提供了PVN中RAS表达的转录组图谱，并确定了针对心脏代谢紊乱治疗策略的潜在细胞靶点。
